Objective We propose a method for a reliable quantitative measure of subjectively perceived occupational stress applicable in any company to enhance occupational safety and psychosocial health, to enable precise prevention policies and intervention and to improve work quality and efficiency. Materials and Methods A suitable questionnaire was telephonically administered to a stratified sample of the whole Italian population of employees. Combined multivariate statistical methods, including principal component, cluster and discriminant analyses, were used to identify risk factors and to design a causal model for understanding work-related stress. Results The model explained the causal links of stress through employee perception of imbalance between job demands and resources for responding appropriately, by supplying a reliable U-shaped nonlinear stress index, expressed in terms of values of human systolic arterial pressure. Low, intermediate and high values indicated demotivation (or inefficiency), well-being and distress, respectively. Costs for stress-dependent productivity shortcomings were estimated to about 3.7% of national income from employment. Conclusions The method identified useful structured information able to supply a simple and precise interpretation of employees’ well-being and stress risk. Results could be compared with estimated national benchmarks to enable targeted intervention strategies to protect the health and safety of workers, and to reduce unproductive costs for firms.